A new therapeutic target for the prevention of heart failure due to aortic stenosis

Heart failure is prevalent in people who have aortic stenosis.

ISLAMABAD, (Online) - Heart failure — a type of cardiovascular disease — affects more than 26 million people around the world.

Heart failure is prevalent in people who have aortic stenosis — a common disorder of the heart valves. More than 20% of older adultsTrusted Source in the United States have aortic stenosis.

Surgery, such as heart valve repair or replacement, is the mainstay of treatment for aortic stenosis. Currently, medications may be used to manage the related symptoms but do not have a significant impact on disease progression.

Now, researchers from Centro Nacional de Investigaciones Cardiovasculares (CNIC) have identified a potential new therapeutic target for the prevention of heart failure linked to aortic stenosis using gene therapy.

Their study was recently published in the journal Basic Research in Cardiology.

What is aortic stenosis?

Stenosis in the heart occurs when the heart valves become narrowed or blocked and do not open properly.

There are four main types of heart valve stenosis:

• Aortic stenosisTrusted Source is the most common type of valve stenosis and refers to a problem with the aortic valve, halting blood circulating from the left ventricle to the aorta.

• Tricuspid stenosisTrusted Source impacts how blood moves between the upper and lower portions of the heart’s right side.

• Mitral stenosisTrusted Source affects how blood flows between the upper and lower portions of the left side of the heart.

• Pulmonary stenosisTrusted Source restricts blood flow from the lower right chamber to the pulmonary arteries and lungs. o

Stenosis of the heart does not always generate noticeable symptoms.

If it does, symptoms may include:

• chest pain

• heart palpitations

• breathing issues

• dizziness

• sleeping problems

• decreased energy

Aortic stenosis mainly affects people over the age of 65. However, it can also occur in people with congenital heart conditions.

Doctors normally use an echocardiogram to diagnose stenosis of the heart.

Beta-3 adrenergic receptor and heart failure

In their study, researchers studied the effect of the beta-3 adrenergic receptorTrusted Source — and its effect on heart failure due to aortic stenosis.

“Beta3 has unique signaling pathways not shared by other beta-adrenergic receptors,” said Dr. Borja Ibáñez, scientific director at the Centro Nacional de Investigaciones Cardiovasculares, a cardiologist at Hospital Universitario Fundación Jiménez Díaz, a member of the Spanish cardiovascular research network (CiberCV), and lead author of this study.

“Among these unique effects, is the protection of mitochondria, the powerhouse of cardiac cells, which are dysfunctional in heart failure conditions,” he told Medical News Today.

“We magnified (these) natural effects by significantly increasing the expression of these receptors in the heart,” he added. “This was possible thanks to a gene therapy approach, where an innocuous virus encoding the gene responsible for the synthesis of these beta3 receptors was directed to the heart. Gene therapy with these new (viruses) has been shown (to be) beneficial in other clinical trials, and thus this approach can be translated into the clinics in the future.”

Beta-adrenergic receptors play an important role in intracellular signaling, helping to regulate body functions such as respiration and heart function.

“The nervous system controls the strength of the heart function,” Dr. Yu-Ming Ni, a cardiologist of Non-Invasive Cardiology at MemorialCare Heart and Vascular Institute at Orange Coast Medical Center in California who was not involved in this study, explained to Medical News Today. “Beta-adrenergic activity regulates the sympathetic nervous system. We often actually want to tamp down that activity in order to help to support the heart, so it’s not overly stimulated and is able to function efficiently, requires less oxygen use, and maintains a healthy heart rate, which is generally between 60 and 100 beats per minute.”

For this study, scientists used gene therapy to overstimulate the beta-3 adrenergic receptor in the hearts of a mouse model. When the mice were subjected to aortic stenosis, researchers found they were protected from heart failure.

And when used in mice that already had aortic stenosis and established heart failure, stimulation of the beta-3 adrenergic receptor helped the mice recover normal heart function.

Welcome news on heart failure treatment

Dr. Paul Heidenreich, professor and vice chair for quality in the Department of Medicine at Stanford University School of Medicine in California and the writing committee chair of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure, told Medical News Today it was exciting to see progress in understanding the mechanism of heart failure due to aortic stenosis.

“Medical therapy for aortic stenosis would be a major scientific advance,” he explained. “Without intervention, surviving patients with aortic stenosis will eventually develop heart failure that will inevitably progress to death.”

“Currently, we do not have a medical treatment for aortic stenosis,” Heidenreich continued. “Surgical and catheter-based valve replacement is the only effective treatment for those with heart failure due to aortic stenosis. Some patients are too frail for these invasive interventions and medical therapy would be their only option for treatment.”

Medical News Today also spoke with Dr. Rigved Tadwalkar, a cardiologist at Providence Saint John’s Health Center in California who was not involved in the study, agreed this research is welcome news.

“Aortic stenosis is ultimately a deadly condition if not intervened upon,” he said. “As aortic stenosis progresses, the left ventricle becomes overwhelmed and the contractile function can diminish. Left ventricular dysfunctionTrusted Source makes aortic stenosis even more dangerous as there is not only obstruction of blood flow to vital organs from the aortic stenosis itself, but also a lack of forward blood flow due to the left ventricle pumping less vigorously. Being able to target the left ventricular dysfunction is a turning point in our search for more sturdy and varied treatment options.” The next steps in research

As for what doctors would like to see as the next steps in this research, Ni stated as the new study is lab-based research with mice, it remains to be seen how beta-3 adrenergic receptor modulation might affect people with heart failure due to aortic stenosis.

“I suspect that with these study findings, there will be working toward building or creating a pharmaceutical drug that targets the beta-3 adrenergic receptor,” he said. “And I’m hoping that work proceeds (so) that we’re able to see if using a medication like that in people with heart failure from aortic stenosis can help them to do better.”

And as this study used a human gene transfer, including the use of an adeno-associated virus to overexpress the beta-3 adrenergic receptor, Tadwalkar said previous research has already shown we can safely use adeno-associated virus in humans to deliver therapy, including in heart failure.